Polyvalent metal complexes of natural polymers

ABSTRACT

IN THE PRESENT INVENTION A POLYMER CONTAINING FUNCTIONAL GROUPS IS REACTED WITH A POLYVALENT METAL CATION IN SOLUTION TO FORM A SALT OF THE POLYMER. PREFERABLY THE POLYMER SALT IS SEPARATED FROM THE SOLUTION BY FREEZEDRYING WHICH PARTICULARLY ENHANCES THE ACTIVITY OF THE SALT. THE POLYMER SALT IS USEFUL FOR THERAPEUTIC PURPOSE SINCE WHEN CONTACTED WITH BILE ACID CONJUGATES, IT BINDS THE CONJUGATE AND PREVENTS REABSORPTION OF BILE ACID BY THE SMALL INTESTINE. PREFERABLY THE SALT OF THE POLYMER CONTAINS AN ENTERIC COATING.

United States Patent 3,563,978 POLYVALENT METAL COMPLEXES OF NATURAL POLYMERS Irving L. Ochs, 28 Franklin St., Annapolis, Md. 21401 No Drawing. Filed May 15, 1968, Ser. No. 735,489 Int. Cl. C08b 11/20 US. Cl. 260-232 16 Claims ABSTRACT OF THE DISCLOSURE In the present invention a polymer containing functional groups is reacted with a polyvalent metal cation in solution to form a salt of the polymer. Preferably, the polymer salt is separated from the solution by freezedrying which particularly enhances the activity of the salt. The polymer salt is useful for therapeutic purposes since when contacted with bile acid conjugates, it binds the conjugate and prevents reabsorption of bile acid by the small intestine. Preferably the salt of the polymer contains an enteric coating.

A most common and serious unsolved problem in medicine today is the problem of cardio-vascular disease. The primary component of this disease is atherosclerosis. Atherosclerosis is a disease in which cholesterol-containing fatty plaques are laid down in the endothelial layer which lines the lumen of the arteries. These fatty plaques progress until the opening in the artery is occluded. When occlusion occurs, the part that is supplied by the artery dies. If this occurs in the heart muscle, a portion of the heart muscle wall dies, and if it is sufficiently large, the patient dies. If it occurs in the brain, a stroke results; if it occurs in an extremity, gangrene results.

There may be several factors involved in the etiology of atherosclerosis, but many experts believe the most common and important factor is high blood fat. There are two main kinds of blood fats involved in this disease, one of which is cholesterol, which is a sterol based on a hydrogenated l,2-cyclopentenophenanthrene ring system. The body normally uses cholesterol to synthesize steroid hormones, bile acids and pre-vitamin D complexes and uses this material in other Ways within the cell walls and cytoplasm. Nervous tissue is composed of thirty percent cholesterol. In disease, the body abnormally used cholesterol in forming fatty plaques. The other fat involved is a common tri-glyceride which is composed of glycerine, a tri-hydroxy alcohol and three fatty acids.

In attempting to lower excess blood fat, a number of measures have been used, principally diet and exercise. Physicians often recommend diminished fat intake, particularly the ingestion of saturated, hard, animal fats and substitute the liquid, vegetable, unsaturated fats. This diet has been effective in a moderate degree in lowering the level of blood cholesterol in those individuals who are prone to a high blood cholesterol level.

In addition, drugs are used to lower blood cholesterol levels. The exact mechanism by which most of these drugs are effective is not known, but thyroxin derivatives, estrogen, nicotinic acid, and a new material, Atromid- S (Merck & 'Co.), have been approved by FDA for therapeutic use. These aforementioned medications are effective in moderately lowering the blood cholesterol level: usually, a ten to twenty percent decrease results. The normal blood cholesterol level is within 100 to 250 milligrams percent, but individuals having a cholesterol level of 700 milligrams percent will not attain a sufficiently beneficial effect by a ten to twenty percent lowering of cholesterol level. Milligrams percent concentration means the number of milligrams of the material in milliliters of blood serum.

A further experimental approach in the treatment of atherosclerosis involves the use of ion exchange resins based on polystyrene and basic nitrogen groups. These resins have been used in medicine for several years, but only recently used in an attempt to lower blood cholesterol level.

The body is capable of synthesizing fifty to sixty grams of bile acid per day from cholesterol. The bile acids are secreted by the liver into the intestine, and ordinarily are instrumental in the emulsification and absorption of fats through the intestinal wall. Cholestyramine, the trade name of the resin previously described, has the faculty of fixing conjugated bile acid so that the reabsorption of bile acids back into the body from the intestine is prevented. The bile acid is excreted with the resin. The body tends to make more bile acid, using the reservoir of cholesterol in the blood. In this manner, the level of cholesterol can be brought down.

Thus, the prevent invention concerns the fixing of bile acids in the intestine, through the use of polyvalent metal complexes comprising organic polymers. The materials of this invention function in a manner similar to the foregoing described Cholestyramine, namely in that they combine with bile acids causing their elimination from the body. The Cholestyramine apparently functions through an ion exchange reaction with the bile acid. The bile acid anion exchanges for the chloride anion on the Cholestyramine. Materials of the instant invention accomplish a coupling reaction between a polyvalent metal ion and bile acids. It has been found that these new organo-metallic complexes are far more effective in removing bile acid from the digestive system than the previously known material. It has been demonstrated that in comparable systems the materials of the instant invention bind bile acids in a superior manner, namely by a magnitude of several-fold. The polyvalent metal of this invention is bound to the organic substrate by at least one of its reacting sites, leaving the other reactive sites available for binding bile acids.

Various polyvalent metals can be utilized via the instant teaching. Further, mixtures of polyvalent metals, each affixed to a high molecular weight organic substrate are herein described.

Ferric iron is a preferred polyvalent ion comprising the instant materials. Further, it has been found that ferric chloride will react selectively with several high molecular weight poly-carboxylic compounds, as represented by carboxymethyl cellulose. The sodium salt of carboxymethyl cellulose reacts with ferric chloride to eliminate sodium chloride to form a carboxymethyl cellulose ironcontaining molecule wherein up to two of the reactive sites of the iron are available for reaction with bile acid conjugates. Bile acid conjugates exist in the intestine as sodium salts, and reaction with the partially hydrolyzed iron cation form of the iron containing materials results in the formation of sodium chloride and a stable iron bile acid carboxymethyl cellulose complex, which is not absorbed through the intestinal wall.

There are several natural and synthetic high molecular weight multi-carboxylic acid materials that can be used as substrates for the polyvalent cations employed. Examples of these include alginates and other hemi-cellulosic materials, as well as a host of synthetic compositions. It is here taught that a complex between materials of this type and at least one functional group on a polyvalent metal, so as to immobilize the polyvalent metal against passage through the intestinal wall, can accomplish the object of this invention through secondary reaction of the reactive sites on the polyvalent metal with bile acid conjugates to form the complexes to be eliminated. The metals comprising the complexes are firmly fixed and are not available for absorption into the blood stream.

It is an object of the present invention to provide a polymeric salt which will react with bile acids. Another object is to provide a process of forming such a polymeric salt. A further object is to provide a particular process for isolating the polymeric salt so as to increase its activity. A still further object is to provide a method of binding bile acid conjugates. A still,further object is to provide the reaction product of the polymeric salt and the bile acid conjugates. Other objects will become apparent as the description of the invention proceeds.

These objects are accomplished by the present invention which provides a process for forming a non-toxic, waterinsoluble polymeric salt which comprises reacting a watersoluble form of a polymer containing reactive functional groups, in an aqueous medium, with a water solution of a polyvalent metal cation to form the water-insoluble salt of the polymer and cation, and thereafter separating the water-insoluble salt of the polymer from the aqueous medium.

The present invention also provides an improvement in the process for the formation of a polyvalent metal salt of a non-toxic polymer having reactive functional groups by reacting the polyvalent metal ion in solution with a water-soluble form of the polymer and thereafter separating the polyvalent metal salt of the polymer from solution, the improvement comprising freeze-drying the mixture to at least partially remove the solvent from the polymer salt.

The present invention further provides a non-toxic polymer salt having the formula (polymer polyvalent metal (OH x wherein x is an integer of from to 3 and wherein all of the valences of the polyvalent metal are satisfied by polymer and (OH) groups.

The present invention also provides a non-toxic polymer salt having the formula (polymer) polyvalent metal (OH) wherein x is an integer of from 0 to 3 and wherein all of the valences of the polyvalent metal are satisfied by polymer and (OH) groups, the said polymer salt being covered with an enteric coating.

The present invention further provides a method of binding bile acid conjugates for therapeutic purposes which comprises contracting bile acid conjugates with a non-toxic polymer salt having the formula (polymer) polyvalent metal (OH) x wherein x is an integer of from 0 to 3 and wherein all of the valences of the polyvalent metal are satisfied by polymer and (OH) groups.

The present invention still further provides the ligand exchange material of a bile acid conjugate and a nontoxic polymer salt having the formula (polymer) polyvalent metal (OH) wherein x is an integer of from 0 to 3 and wherein all of the valences of the polyvalent metal are satisfied by polymer and (OH) groups.

The term non-toxic signifies that the material when ingested has no substantial deleterious effects upon the body in the amount normally used i.e. up to about 50 grams/day (solid weight). The expression polymeric salt means that a reaction product has formed between the polymer and the polyvalent metal cation. The binding is ionic and the polymer salt is quite stable under normal conditions. The water-solubility and insolubility as used herein is determined by whether or not the material is soluble in water (standard conditions) to the extent of one gram per liter. If the material is soluble in water to the extent of one gram per liter, it is considered water-soluble for the purpose of this invention. If it is not soluble to the extent of one gram per liter, it is waterinsoluble.

The term funtcional group is used to signify that the group will react with the polyvalent metal cation in solution to form a salt. Preferably, the functional group is the carboxylic acid group COOH or the sulfonic acid group SO H or salts of such groups. The polyvalent metals which can be used in the practice of the present invention, are preferably the trior tetra-valent materials, but in some instances the divalent cations are equally suitable. Among such polyvalent materials are ferric and ferrous iron, aluminum, chromium, antimony, calcium, magnesium, zirconium, tin, bismuth and hydroylysis products of such materials. Other polyvalent metal cations are equally suitable. The freeze-drying technique employed in the present invention is conventional in the art and merely signifies that the material is at least partially frozen and the ice is then sublimed. Generally, the freeze-drying is carried out under a vacuum. Such processes are well known in the art and described in U.S. Pats. 2,225,627, 2,292,447, 2,400,748, and 2,435,503.

The ligand exchange material which forms is stable under the conditions normally encountered in the mammalian intestinal tract and is excreted. The formation of the ligand exchange material prevents the bile from absorbing fat through the intestinal wall.

The bonding of the polyvalent metal to the polymer may be intraor inter-molecular bonding. Thus, when two bonds of the metal are joined to the polymer, the bonds may both be joined to a single polymer molecule or one bond to each of two polymer molecules. The present invention contemplates and includes both types of bondmg.

The expression enteric coating is conventional and merely means that the product is covered with a material which allows the product to be inactive until it reaches the small intestine. These materials, such as capsules of coated gelatine, coatings of stearic acid and the like, are well known and obvious to those skilled in the art. Any of these materials may be selected as desired.

The following examples are given to illustrate the invention and are not intended to limit it in any manner. In the examples, all parts are given in parts by weight unless otherwise expressed.

EXAMPLE 1 (A) Preparation of active Fe+++ carboxymethyl cellulose substrate 9.607 grams of a commercially available sodium carboxymethyl cellulose is weighed into a two liter beaker. By analysis the sodium carboxymethyl cellulose contains 3.20 milliequivalents of sodium per gram of material. One liter of distilled water is now added to the beaker from a graduate and the sample is stirred with a magnetic stirrer until it dissolves which usually takes about one hour.

Next, a second two liter beaker is prepared containing 600 ml. of distilled water. Using a 50 ml. buret, 30.19 ml. of 1.0184 molar ferric chloride solution is added to the distilled water to give a dilute ferric chloride solution in which the ferric ion concentration is 0.0488 molar. The dilute ferric chloride solution is unstable hydrolytically and should be used as soon as prepared.

To accomplish the synthesis, the sodium carboxymethyl cellulose solution is slowly poured into the dilute ferric chloride solution with constant and rapid stirring. This gives a gelatinous precipitate of hydrolyzed ferric carboxymethyl cellulose. The precipitate and solution are allowed to stand overnight and then they are filtered with suction on a Buchner funnel. The filter cake composed of insoluble gelatinous ferric carboxymethyl cellulose is washed on the filter with two separate ml. portions of distilled water. The filtrate and washings are reserved in a 2 liter volumetric flask.

(B) Thermal drying of product The product consisting of the gelatinous filter cake is transferred to a jar and then vacuum dried at =60 C. in a vacuum oven. This drying takes 2 days during which period the voluminous gel shrinks and dehydrates. Final dehydrated volume of the dried gel is about 5% of the initial hydrated volume.

The combined filtrate and washings (reserved above) are diluted to volume with distilled water and mixed. A 25.0 ml. aliquot is withdrawn, diluted with about 75 ml. of water, and ammonium hydroxide is added to precipitate ferric hydroxide. This ferric hydroxide is filtered off and determined gravimetrically by the conventional procedure well known to those skilled in the art of analytical chemistry.

The aliquot gave 0.0135 gram of ferric oxide, Fe O From this it is calculated that the washings and filtrate contained 13.53 millimols of iron. The millimols of iron used are 30.19 1.0184=30.75. By difference then 30.75 13.53 gives 17.22 millimols of iron reacted with the sodium carboxymethyl cellulose. This is where 3.20 is the carboxy content of the raw material Na carboxymethyl cellulose. This value of 1.79 for the mole ratio (F indicates that the reacted Fe species in the product is 79 mole percent FeOH++ and 21 mole percent Fe(OH) V The general formulae for the products are thus 21% (carboxymethyl cellulose)--Fe(OH) and 79% (carboxymethyl cellulose)=FeOH that is,

(carboxymethyl cellulose) Fe(OH) Where x has an average value of 1.21 and wherein the double valence of the iron may be satisfied by one or two carboxy groups of the carboxymethyl cellulose molecules. The hydroxy groups are thus available for reaction with conjugated bile salts as is hereinafter demonstrated.

(C) Test for efiicacy of thermally dried Fe+++ carboxymethyl cellulose as an active absorbent for conjugated bile salts in vitro A sample of human bile obtained from a gall bladder operation is used in this work. A 2.0 ml. portion of the bile is transferred to a m1. volumetric flask, diluted to volume with distilled water and mixed. This solution is used as the standard solution to supply conjugated bile acids for testing. Analysis of the solution is by the method of Levin et al., Analytical Chemistry, vol. 33, No. 10, p. 1407 (1961).

To test a given substrate, 3.00 milliliters of standard bile solution, as prepared above, is measured into a test tube. Next, 100 to 300 milligrams of the substrate is added to the bile solution and mixed vigorously for five minutes. After a period of 105 minutes, 3.0 milliliters of distilled water is added and the system mixed. This gives a total volume of 6.0 milliliters. The mixture is filtered and a 2.0 milliliter aliquot of the filtrate is introduced into a clean test tube. Next, 2.0 milliliters of furfural solution is added to the test tube, followed by 4.0 milliliters of 24-normal sulfuric acid. The test tube is now heated for 13 minutes at 65 C. according to the method of Levin et al. At the end of this heating period, the test 5 tube is cooled in crushed ice, and 5.0 milliliters of glacial acetic acid is added. After mixing, the color is measured in a filter photometer at a wavelength of 620 millimicrons. The amount of conjugated bile acid present is determined against the calibration curve described by Levin et al. A

The last entry in the above table shows the blank car- 25 ried through this procedure. 0.325 milligram of conjugated cholic acid was found as a blank. The other entries in the table show less cholic acid than this. The difference between 0.325 and the other numbers represents the cholic acid bound by the substrate. The percent of cholic acid removed is also given in the table.

(D) Freeze-drying of product The procedure of Example 1(A) is repeated to give a gelatinous ferric carboxymethyl cellulose in the wet form on a filter. 100 grams of the wet cake are transferred to a 500 ml. round-bottomed flask having a 24/40 groundglass joint. The contents are frozen solid in a bath of acetone and Dry Ice. The ground-glass joint is then attached to a conventional laboratory freeze-drying apparatus. Vacuum (2 mm. of Hg) is applied and the ice sublimes and is collected in a central collection zone. The product dries in from about 24 to 36 hours to give about 8 grams of product (dry weight).

(E) The test for efficacy of freeze dried Fe carboxymethyl cellulose as an active absorbent for conjugated bile salts in vitro A sample of the freeze-dried product is tested for eflicacy as described in Example 1(C) above.

With no CMC/Fe substrate present 0.480 mg. of cholic acid are found. The difference between column 2 and 0.480 represents the cholic acid left in solution. Thus most of it is absorbed. The activity of the freeze-dried product is considerably greater than the thermally dried product.

(F) Encapsulation with stearic acid binder 98 grams of the ferric carboxymethyl cellulose obtained above in Example 1(D) is ground in a mortar and pestle with 2 grams of stearic acid. As the mixture becomes compacted (after about 5 minutes) the mixture is transferred to a conventional laboratory spherical pill making machine. About 1 gram of the material is compressed at 2000 lbs. per square inch pressure into a spherical ball having a diameter of about /2 inch. The resulting spherical ball has a polished somewhat greasy surface which indicates that under the pressure employed in the press the stearic acid tends to flow and coat the individual particles of the ferric carboxymethyl cellulose.

The stearic acid coating of the ferric carboxymethyl cellulose is stable to an acid medium, as found in the stomach, but readily forms a soluble stearate salt in the slightly basic medium of the small intestine to release the active ferric carboxymethyl cellulose to react with the bile acid conjugates. The reaction of the ferric CMC with the bile acid conjugates forms a complex which is insoluble and passes from the intestines in the normal manner. The formation of the complex prevents the bile from aiding in the digestion of fats in the intestines.

The product is also encapsulated by filling enteric coated gelatine capsules with the product. Such capsules are very useful in avoiding contact of the product with the acid medium normally found in the stomach.

EXAMPLE 2 The procedure of Examples 1(A) and 1(B) is repeated with the exception that 9.0755 grams of sodium carboxymethyl cellulose are employed with 9.51 ml. of 1.0184 molar ferric chloride solution, giving a diluted ferric chloride solution in which the ferric ion concentration is 0.0159 molar. All other conditions were the same as in Examples 1(A) and 1(B).

Analysis showed a ratio of moles COOH) moles Fe of 3.04. This indicates the reacted Fe species to be Fe+ of the general formula carboxymethyl celluloseEFe This material is also active towards bile acid conjugates.

EXAMPLE 3 The procedure of Examples 1(A) and 1(B) are repeated with the exception that 10.0870 grams of sodium carboxymethyl cellulose and 15.85 ml. of 1.0184 molar ferric chloride solution, giving a dilute ferric chloride solution in which the ferric ion concentration is 0.0262 molar, are used. All other conditions are the same as in Examples 1(A) and 1(B).

Analysis showed a ratio of moles COOH moles Fe of 2.30. This indicates the reacted iron species to be 70% FeOH++ and 30% Fe+ or 70% carboxymethyl cellulose=FeOH and 30% carboxymethyl celluloseEFe that is,

(carboxymethyl cellulose) Fe(-OH) where x has an average value of 0.7.

This material is also active towards bile acid conjugates.

EXAMPLE4 COOH A1+3 This indicates the reacted Al species to be 70% OAl(OH) and 30% Al(OH)++ or 8 70% carboxymethyl cellulose Al(OH) and 30% carboxymethyl cellulose=AlOH that is,

(carboxymethyl cellulose) Al(OH) where x has an average value of 1.7.

The turbidity of reaction mixture of the bile acid conjugates with the polymer salt prevents a quantitative analysis of the mixture but a qualitative analysis shows that the polymer salt reacts with the bile acid conjugates.

EXAMPLE 5 The procedure of Examples 1(A) and 1(B) is repeated with the exception that 10.0061 grams of sodium carboxymethyl cellulose is reacted with 16.01 ml. of 1.0000 molar aluminum chloride solution, giving a dilute aluminum chloride solution in which the aluminum ion concentration is 0.0259 molar. All other conditions remain the same.

Analysis showed a product with the mole ratio COOH A1+a This indicates that the reacted aluminum species is Al(OH)++ giving a polymer salt of the general formula (carboxymethyl cellulose) Al(--OH) where x has an average value of 1.0.

EXAMPLE 6 COOH This indicates that the reactive aluminum species is 100% Al+ of the general formula carboxymethyl celluloseEAl While the particular carboxymethyl cellulose employed in Example 1 contained 3.20 milli-equivalents of sodium per gram of polymer, other carboxymethyl celluloses with different concentrations of sodium can be employed. If one uses a carboxymethyl cellulose with more carboxyl groups per repeating unit, the amounts of iron employed can be increased and the final result is a product with even higher iron concentration. Conversely, if one employed a sodium carboxymethyl cellulose of low sodium content, lesser amounts of iron are reacted and the final product is lower in iron. As seen from the foregoing examples, the concentration of metal salts used ranged from 0.0159 to 0.0508 mole of metal ion per liter of water. Also, as shown in the foregoing examples, the value of x can range from 0 to 3 depending on the particular metal salt used and specific conditions of preparation. The examples specifically illustrate a range of x from 0.7 to 1.7 using trivalent metal salts. Values of x over 2. but not over 3 may be obtained using tetravalent metal salts.

Other natural polymers can also be used. Sodium alginates, which occur naturally in seaweed, are one type of suitable polymer. In the case of sodium alginate, the repeating carbohydrate unit has a lower equivalent weight than the equivalent weight of sodium carboxymethyl cellulose. These equivalent weights, or molecular weight per sodium atom, are 242.16 for sodium carboxymethyl cellulose and 198.11 for sodium alginate. The lower equivalent weight of sodium alginate polymer means that higher amounts of iron can be reacted along the polymer chain as compared to sodium carboxymethyl cellulose. This is an advantageous feature for effective performance in some applications of this invention.

As a further example of a naturally occurring polymer, carrageenan, also known as Irish Moss, can be used in this invention. This substance is commercially used in toothpaste, ice creams, and similar products. It contains reactive sulfonic acid groups, along a polysaccharide chain. Ferric cations can be reacted through the sulfonic acid groups with various stages of hydrolysis. This is accomplished through the use of a sodium salt, as before mentionesd. Likewise, polymeric materials, either natural or synthetic, may be used in this invention. They only require a carboxyl or other acidic group of anionic struc ture for reaction with iron or other polyvalent cations, as herein described.

A specific example of a synthetic polymer suitable for use in this invention is a co-polymer prepared by copolymerizing styrene and maleic anhydride. When this copolymer is subjected to alkaline hydrolysis, the anhydride rings open up to give sodium carboxylate groups, which are reactive towards polyvalent cations, as taught in this invention. Co-polymers of styrene and maleic anhydride, known commercially as Stymer, are available with l to 1 mole ratios of styrene to maleic groups. A still further example of synthetic polymers suitable for use in this invention are polyacrylic acid materials, where the carboxyl groups are reacted with a polyvalent cation, as described.

Antimony tri-chloride or bismuth tri-chloride are water soluble materials which may also be used as polyvalent cations in compositions comprising polymeric substrates. For example, antimony tri-chloride in aqueous solution can be reacted with sodium carboxymethyl cellulose or sodium alginate to give gelatinous precipitates comprising compositions of this invention.

Many other equivalent modifications will become apparent to those skilled in the art from a reading of the foregoing without a departure from the inventive concept.

What is claimed is:

1. A process which comprises reacting an aqueous solution of a water-soluble form of a non-toxic polymer selected from the group consisting of carboxymethyl cellulose, naturally occurring alginates, naturally occurring carrageenin and mixtures thereof with a dilute aqueous solution containing 0.0159 to 0.0508 mole per liter of a metal cation selected from the group consisting of Fe+ Al+ Cr+ Sb+ Bi+ Zr+ Sn+ and Ti+ or mixtures thereof to form a water-insoluble salt of the said polymer and said cation or cations wherein all of the valences of the polyvalent metal are satisfied by the COO- or -SO groups of the polymer and OH groups, and thereafter separating the water insoluble salt of the polymer from the aqueous reaction medium.

2. The process of claim 1 wherein the polyvalent metal cation is Fe+++.

3. The process of claim 1 wherein the polyvalent metal cation is Al+++.

4. The process of claim 1 wherein the non-toxic polymer is carboxymethyl cellulose.

5. Process as defined in claim 1, including the additional step of freeze-drying the separated polymer salt.

6. The process of claim 5 wherein the polyvalent metal cation is Fe+++.

10 7. The process of claim 5 wherein the polyvalent metal cation is Al+++.

8. The process of claim 5 wherein the non-toxic polymer is carboxymethyl cellulose.

9. A non-toxic polymer salt 'having the formula:

(polymer) M (OH) x wherein (polymer) represents a member of the group consisting of carboxymethyl cellulose, naturally occurring alginates, naturally occurring carrageenin and mixtures thereof; M represents a metal cation selected from the group consisting of Fe, Al+ Cr+ Sb, Bi+ Zr+ Sn+ and Ti+ or mixtures thereof; at is a positive number having an average value of from 0.7 to 1.7 and wherein all of the valences of the polyvalent metal cation are satisfied by the CO0 or -SO groups of the polymer and OH groups.

10. The polymer salt of claim 9 wherein the polyvalent metal is trivalent iron.

11. The polymer salt of claim 9 wherein the polyvalent metal is trivalent aluminum.

12. The polymer salt of claim 9 wherein the non-toxic polymer is carboxymethyl cellulose.

13. The liquid exchange product of a bile acid conjugate and a non-toxic polymer salt as defined in claim 9.

14. The ligand exchange materials of claim 13 wherein the polyvalent metal is trivalent iron.

15. The ligand exchange material of claim 13 wherein the polyvalent metal is trivalent aluminum.

16. The ligand exchange material of claim 13 wherein the non-toxic polymer is carboxymethyl cellulose.

References Cited UNITED STATES PATENTS 2,225,627 12/ 1940 Flosdorf 34-24 2,435,503 2/1948 Levinson et al. 34-5 2,686,777 8/ 1954 Wimmer 260209 2,691,596 10/1954 Nack et al. 10634 2,842,451 7/1958 Grummit et a1 106194 2,849,426 8/1958 Miller 26079.5 3,351,581 11/1967 Schweiger 260209.5 2,853,414 9/1958 Wimmer 19722 2,856,366 10/1958 Novak et al. 252-363.5 3,000,872 9/1961 Novak 260209 3,005,802 10/ 1961 Sellers 260-78.5 3,085,943 4/1963 Fowler et al l6768 3,234,209 2/1966 Floramo 260209 3,262,847 7/1966 Flodin et al. 16753 3,349,079 10/1967 Freedman 2602096 3,372,979 3/ 1968 Reinhardt et al 8-120 3,378,541 4/1968 Colquhoun et al. 260209 3,386,921 6/1968 Schweiger et al. 252-316 3,396,158 8/1968 Hang 2602095 3,428,584 2/1969 Riley 26015 MAURICE I. WELSH, JR., Primary Examiner M. I. MARQUIS, Assistant Examiner US. Cl. X.R. 

